Use of 2-(cyanoalkyl)amino-4-amino-6-substituted-s-triazines for inducing depressant effects in animals

ABSTRACT

USE OF 2-(CYANOALKYL)AMINO-4-AMINO-6-SUBSTITUTED-STRIAZINES FOR INDUCING DEPRESSANT EFFECTS IN ANIMALS.

"United States Patent O USE OF 2-(CYANOALKYL)AMINO-4-AMINO-6-SUB- STITUTED-s-TRIAZINES FOR INDUCING DE- PRESSANT EFFECTS IN ANIMALS James R. Albert and Jim K. Kodama, Modesto, Califl, assignors to Shell Oil Company, New York, N.Y., a corporation of Delaware No Drawing. Filed Apr. 17, 1968, Ser. No. 721,924

Int. Cl. A61k 27/00 U.S. Cl. 424-249 18 Claims ABSTRACT OF THE DISCLOSURE Use of Z-(cyanoalkyl)amino-4-amino-6-substituted-striazines for inducing depressant effects in animals.

BACKGROUND OF THE INVENTION This invention relates to a method of inducing depressant efiects in animals using certain s-triazines. More particularly it relates to the use of certain s-triazines as analgesics, muscle relaxants, anticonvulsants and tranquilizers and to pharmaceutical and veterinary compositions containing such triazines.

A considerable number of naturally occurring alkaloids and synthetic chemicals are available as useful analgesics, anticonvulsants and muscle relaxants. Repeated administration of many such analgesics creates the potential danger of drug addiction. The need for effective analgesics which minimize the hazards of drug addiction has long been recognized.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel method for inducing depressant effects in mammals. These depressant effects include sedative, analgesic, muscle relaxant, anticonvulsant and tranquilizing effects. Another object of the invention is to provide a novel method of pain control with minimum hazard of drug addiction. Yet another object is to provide a novel method for inducing depressant effects in mammals with certain 2-(cyanoalkyl)amino 4 amino-6-substituted-s-triazines. The provisions for supplying the art with novel pharmaceutical and veterinary compositions capable of inducing neurological depressant effects in mammals forms another object.

These and other objects are accomplished by administering to a mammal an effective dosage of a 2-(cyanoalkyl)amino-4-amino 6 substituted-s-triazine of the formula wherein R is hydrogen or alkyl of 1-5 carbon atoms;

R is hydrogen or alkyl of 13 carbon atoms;

R is hydrogen, alkyl of 1-5 carbon atoms, alkoxy of 13 carbon atoms, methoxyalkyl of 2-5 carbon atoms or w-alkenyl of 3-5 carbon atoms;

R is hydrogen or alkyl of 1-3 carbon atoms; and

Patented Jan. 5, 1971 "ice ----OR,, and R R and R are alkyl of 1-3 carbon atoms.

Representative species of the above s-trazines are:

2- l-cyanol -methylethyl) amino-4-ethylamino-6-trichloromethyl-s-triazine 2- 1-cyanol-methylethyl amino-4-amino-6-chloros-triazine 2-( 1-cyano-1,2-dimethylpropyl)amino-4-amino-6-chloros-triazine 2-( l-cyano- 1 -methylethyl) amino-4-methylamino-6- chloro-s-triazine 2-( l-cyano-l -methylpropyl) amino-4-methy1amino- 6-chloro-striazine 2- l-cyano-l ,Z-dimethyl-propyl) amino-4-methylamino- 6-chloro-s-triazine 2- 1 -cyano-2-methylpropyl amino-4-methylamino-6- chloro-s-trazine 2.-( l-cyano-1,3-dimethy1butyl) amino-4methylamino- 6-chloro-s-triazine 2- I-cyano- 1 ,Z-dimethylpropyl amino-4-methylamino- 6-chloro-s-triazine 2-( l-cyanoethyl amino-4-ethylamino-6-chlor0-s-triazine 2-( l-cyanol-methylbutyl amino-4-ethylamino-6-chloro s-triazine 2-( l-cyano-l ,Z-dimethylpropyl amino-4-ethylamino- 6-chloro-s-triazine 2- l-cyanol-methylpropyl) amino-4-propylamino-6- chloro-s-triazine 2-( l-cyanol-methylethyl) amino-4-buty1amino-6-chloros-triazine 2-( cyanomethylamino -4-isopropylamino-6-chloros-triazine 2- l-cyanoethyl) amino-4-isopropylamino-6-chloros-triazine 2-( l-cyano-1,2-dimethylpropyl) amino-4-isopropylaminoo-chloro-s-triazine 2-( l-cyano-l-methylethyl) amino-4-allylamino-6-chlor'os-triazine 2- l-cyano-l-methylethyl) amino-4-di'methylamino- 6-chloro-s-triazine 2-( l-cyano-l-methylethyl amino-4-diethylamino-6- chloro-s-triazino 2-( l-cyano-l-methylpropyl) amin0-4-diethylamino-6- chloro-s-triazine 2-( l-cyano-l-methylethyl) amino-4-isopropylamino- -ethylamino-s-triazine 2- l-cyano-l-methylethyl) amino-4,6-bis- (ethylamino s-triazine 2-( l-cyano-l-methylpropyl) amino-4,6-bis- (ethylamino) s-triazine 2-( l-cyano-l-methylethyl) amino-4-amino-6-azidos-triazine 2-( l-cyano-l ,Z-dimethylpropyl) amino-4-amino-6-azidos-triazine 2-( 1-cyano-1-methylethyl)amino-4-methylamino-6- azido-s-triazine 2-( 1-cyano-1,2-dimethylpropyl)amino-4-methylaminofi-azido-s-triazine 2-( l-cyano-l -methy1hexyl) amino-4-methylamino-6- azido-s-triazine 2-( l-cyano-l-methylpropyl) amino-4-methylamino-6- azido-s-triazine 2-( l-cyano-l-methylethyl amino-4-ethylamino-6-azidos-triazine 2- l-cyano- 1 -methylpropyl) amino-4-ethylamino-6-azidos-triazine 2- 1 cyano-1,2-dimethylpropyl) amino-4-ethylamino- 6-azido-s-triazine 2-( l-cyano-l-methylethyl) amino-4-isopropylamino- 6-azido-s-triazine 2-( 1-cyano-1-methylethyl)amino-4-diethylamino-6-azidos-triazine 2-( l-cyano-l-methylpropyl amino-4-amino-6-methylthio-s-triazine 2-( l-cyanol-methylpropyl arnino-4-methylamino-6- Inethylthio-s-triazine 2- l-cyano-1,2-dimethylpropyl) a-mino-4-methylamino- 6-methylthio-s-triazine 2-( l-cyano-l-methylethyl) amino-4-ethylarnino-6-methylthio-s-triazine 2- l-cyanol-methylethyl amino-4-ethoxyamino-6-methylthio-s-triazine 2- l-cyano-l -'methylethyl) amino-4-methylamino-6- cyano-s-triazine 2-( l-cyanol -methylethyl) amino-4-ethylamino-6-cyanos-triazine 2- l-cyano-l-methylpropyl) amino-4-ethylamino-6- cyano-s-triazine 2- l-cyano- 1 -methylethyl) amino-4-isopropylamino-6- cyano-s-triazine 2- l-cyano-l -methylpropyl amino-4-amino-6-methoxys-traizine 2-( l-cyano- 1 -methylethyl amino-4-amino-6-methoxys-triazine 2- l-cyanol -ethylpropyl amino-4-methylamino-6- methoxy-s-triazine 2-( l-cyano-l-methylethyl amino-4-methylamino-6- methoxy-s-triazine 2- l-cyano-1,2-dimethylpropyl) amino-4-methylamino- 6-methoxy-s-triazine 2-( l-cyanol-methylpropyl amino-4-ethylamino-4-ethylamino-6- methoxy-s-triazine 2-( l-cyano- 1 -ethylpropyl) amino-4-ethylamino-6- methoxy-s-triazine 2-( l-cyanoethyl amino-4-ethylamino-6-methoxys-triazine 2- l-cyano-1-methylethyl)amino-4-(3-methoxypropylamino) -6-methoxy-s-triazine Compositions according to the present invention also comprise a pharmaceutical carrier which may either be solid material or a liquid. Preparations for oral administration can be liquids or solids or any combination of these forms, such as syrups, elixirs, powders, capsules, or tablets. Preparations for administration of the active agent in unit dose form can be powders, compressed tablets, or a powder enclosed in a suitable capsule of absorbable material such as gelatin. The powders or compressed tablets may also comprise suitable excipients and/ or diluents such as starch, lactose, stearic acid, magnesium stearate, dextrin or polyvinylpyrrolidone.

Preparations for topical application may be in the form of a liquid, a powder, a salve, or as an aerosol.

Preparations for parenteral administration may be sterile solutions or suspensions in liquids such as water, physiological saline, benzyl alcohol, ethyl oleate, methylcellulose, dimethyl sulfoxide or other liquid excipients known in the pharmaceutical and veterinary formulation art.

Any of the above preparations may contain the triazines of the invention or may contain in addition other pharmaceutically active agents. For example, for topical application it may be desirable to include a germicide and/or a fungicide.

The unit dosage or therapeutically effective quantity of the triazines used according to this invention as analgesics, muscle relaxants, anticonvulsants and/or tranquilizers can vary over wide limits. For oral or parenteral administration in some cases, as little as 0.01 milligram of the active material per kilogram of body weight can be effective in the reduction of pain or in effecting sedation and muscle relaxation, while seldom will a dosage in excess of about 500 milligrams per kilogram of body weight be required. In general, for oral administration, the eifective dosage will be from about 1.0 to 200 milligrams per kilogram of body weight, while for parenteral administration, the effective dosage will be from about 0.10 to about 100 milligrams per kilogram of body weight. Each dosage unit forrneach capsule, tablet, ampoule, or prescribed dosecan contain from about 1 percent to about percent of active material, based upon the total weight of the formulation and preferably contains from about 2.5 percent to about 50 percent of the active material, on the same basis. Of course, it is possible to administer the therapeutics without the use of a pharmaceutical carrier.

The therapeutic agents used according to the invention can be administered either prior to or after the onset of the condition to be treated, such as when they are used as: analgesics for the amelioration of pain; motor depressants or tranquilizers to relieve nervous tension; central depressants to reduce hyperexcitability and induce sedation; or as muscle relaxants for relief from pain and discomfort of disorders involving muscle spasms.

PREPARATION The s-triazines of this invention may be prepared by any of the conventional methods for preparing these types of compounds. The following descriptions are illustrative of some of the methods that may be used.

The most convenient starting materials for the s-triazines of the invention are cyanuric chloride and 2,4,6- tris-(trichloromethyl)-s-triazine. From these s-triazines the various compounds of the invention are prepared by replacement of the chloro or trichlorornethyl groups with the various groups depicted in Formula I. For convenience, the methods will generally be described using cyanuric chloride, although it is to be understood that 2,4,6- tris-(trichloromethyl)-s-triazine can be used to form the corresponding trichloromethyl-s-triazines.

Thus, 1 mol of cyanuric chloride can be reacted with 1 mol of an a-amino nitrile of the formula R1 (III) in the presence of a hydrogen halide binding agent such as aqueous sodium hydroxide and subsequently with 1 mol of ammonia or amine of formula HNR R also in the presence of aqueous sodium hydroxide. The remaining chloro substituent may be replaced by the alkylamino group (-NHRQ by the use of primary amines by the previously described techniques. R, R R R and R have the same meanings as in the s-triazines of Formula I.

These u-amino nitriles are produced by conventional methods, such as, for instance, by first reacting ketones or aldehydes with hydrocyanic acid in the presence of an alkaline catalyst to form the corresponding cyanohydrin and reacting the latter with ammonia to produce the desired amino nitrile. The synthesis also can be carried out in one step by reacting the ketone or aldehyde, hydrocyanic acid and ammonia with or without a diluent. A mixture of ammonium chloride and alkali metal cyanide can be used instead of free hydrocyanic acid. In the latter instance the reaction is carried out in the presence of water. The aamino nitriles are water white liquids which can be distilled under vacuum.

The alkyl mercapto derivatives can, for example, be produced by reaction of the corresponding chloro substituted s-triazines with an alkyl mercaptan in the presence of an acid binding agent. It also is possible to start from 2-alkyl-mercapto-4,6-dichloro-s-triazines which are sequentially reacted with an cit-amino nitrile in the presence of an acid binding agent and in the presence of an amine again in the presence of an acid binding agent. It furthermore is possible first to introduce an amino group into the s-triazine and then the alkyl mercapto group and finally again an amino group (starting, for example, from cyanuric chloride).

The alkoxy derivatives, for instance, can be produced in high yields by reacting the corresponding chloro substituted s-triazines with sodium or potassium alcoholates in an alcohol at raised temperatures and, if desired, raised pressures. The cyanuric chloride also can first be converted to the 2-alkoxy-2,4-dichloro-s-triazine by conventional methods, for example, by reaction of cyanuric chloride with alcohol in collidine and then reacting the intermediate with the u-amino nitrile and the amine in any desired sequence.

Azido s-triazines of the type concerned can be produced by reaction of a chloro-s-triazine with an alkali metal or ammonium azide in dimethyl formamide or dimethyl sulfoxide or even better by reacting such azides with a quaternary methyl ammonium compound in water.

Another method for the production of the compounds according to the invention involves starting from a 2- amino-, alkylamino-, methoxyalkyl amino, alkoxy amino, w-alkenyl amino or cyanalkyl amino-2,4-dichloro-s-triazine and converting such compounds to the corresponding 4-azido-6-chloro-s-triazine by reaction with an aqueous alkali metal azide solution in the presence of appropriate solvents such as acetone or tetrahydrofuran. The intermediate azido compound is then converted to the desired product with an tat-amino nitrile, ammonia or an amine.

The cyano substituent is most conventionally introduced by reacting the 2-(cyanoalkyl)amino-4-amino (NR R 6-chloro-s-triazine with sodium cyanide in a suitable organic solvent such as tetrahydrofuran in the presence of a hydrogen halide binding agent at moderate temperatures.

The following examples are illustrative of the methods for preparing the compounds of this invention.

EXAMPLE I 18 g. of u-amino-isobutyronitrile was added to 35.9 g. of 2,4 bis-(trichloromethyl)-6-ethylamino-s-triazine in 200 ml. of methanol. The mixture was held at 50 C. for a period of 6 hours. After adding water, the crystalline product precipitated. After drying under vacuum and recrystallizing from ligroin, 21.4 g. of white crystalline 2- (1 cyano-l-methylethyl)amino-4-ethylamino-6-trichloromethyl-s-triazine, M.P. 6465 C., was obtained.

EXAMPLE II 184.5 g. of cyanuric chloride was suspended in 750 m1. of acetone and the suspension cooled to C.; then 85.7 g. of a-amino-isobutyronitrile (1.02 mol) was added gradually while maintaining a temperature not above 5 C. Thereafter a solution of 40 g. NaOH in 100 ml. of H 0 was added gradually, care being taken that the pH did not rise above 8. Then 200 g. of a 17% ammonia solution was added gradually without external cooling. The temperature gradually rose to 3035 C. The mixture was stirred until it reacted neutrally. The acetone was then drawn 01f under vacuum and water added to the residue. The resulting thick crystal paste was filtered olf, washed with water and dried under vacuum at 50 C. The yield of 2-(1- cyano l-rnethylethyl)amino-4-amino-6-chloro-s-triazine was 174.4 g. (82% of theory).

Thin layer chromatogram: 98%.

Analysis.C H N Cl, mol. wt. 212.5: Calculated (percent): C, 39.5; H, 4.3; N, 39.5; C1, 16.7. Found (percent): C, 39.7; H, 4.4; N, 39.5; C1, 16.6.

EXAMPLE III 184.5 g. of cyanuric chloride was suspended in 1 liter of tetrahydrofuran and the suspension cooled to 0 C.

While maintaining this temperature and stirring, 100 g. of a-aminoisovaleronitrile was first added gradually and then g. of 50% aqueous NaOH added gradually. The mixture quickly became neutral. The cooling was suspended and g. of a 50% aqueous ethylamine solution was added, permitting the temperature to rise, and then again 80 g. of 50% aqueous NaOH gradually added thereto. The maximum temperature reached was 45 C. After processing analogously to Example II, 240.5 g. of the white product, 2-(l-cyano-l-methylpropyl)amino-4- ethylamino--chloro-s-triazine, of melting point of 139- 141 C. was obtained.

Analysis.C H N Cl, mol. wt. 254: Calculated (percent): C, 47.2; H, 5.9; N, 33; Cl, 13.9. Found (percent): C, 47.2; H, 6; N, 33.1; C1, 14.1.

EXAMPLE IV 240.5 g. of 2-(l-cyano-l-methylethyl)amino-4-ethylamino-6-chloro-s-triazine was added to 1 liter of methanol containing 54 g. of sodium methylate at 30-35 C. The reaction was weakly exothermic. The reaction mixture was kept at 30-35 C. for 4 hours and then at 60 C. for 1 hour. The solution then reacted neutral. The methanol was evaporated off under vacuum and the residue taken up in water and the crystals formed filtered off, washed with water and dried to yield 227 g. of 2-(1-cyano-lmethylethyl)amino 4 ethylamino-6-methoxy-s-triazine, M.P. 138 C.

Analysis.C H N O, mol. wt. 236: Calculated (percent): C, 50.8; H, 6.8; N, 35.6. Found (percent): C, 50.7; H, 6.9; N, 35.7.

EXAMPLE V 282.5 g. of 2-(l-cyano-l-methylhexyl)amino-4-methylamino-6-chloro-s-triazine was added to 1 liter of isopropanol and 70 g. of sodium azide and ml. of an aqueous solution of 20 g. of trimethylamine added thereto. The temperature rose slightly. The mixture was then heated for 4 hours at 40-45 C. The solvent was then evaporated olf under vacuum and the residue taken up in water. After filtering off the resulting crystals, washing and drying, 267.5 g. of 2-(l-cyano-l-methylhexyl) amino-4-methylamino-6-azido-s-triazine M.P. 97-98 C., was obtained.

Analysis.-C H N mol. wt. 289: Calculated (percent): C, 49.8; H, 6.6; N, 43.6. Found (percent): C, 49.7; H, 6.8; N, 43.3.

EXAMPLE VI An aqueous solution of g. of isopropylamine in 600 ml. of H 0 was placed in a 2 liter autoclave and 240.5 g. of 2 (l cyano l-methylethyl)amino-4-ethylamino-6-chloro-s-triazine added thereto. After closing the autoclave it was heated to 100-110 C. for 4 hours. After processing the reaction mixture in a manner analogous to that of the preceding examples, 253 grams of Z-(l-cyano- 1 methylethyl)amino-4-ethylamino-6-isopropylamino-striazine, M.P. 91-92 C., was obtained.

Analysis.C H N mol. wt. 263: Calculated (percent): C, 54.8; H, 8.0; N, 37.2. Found (percent): C, 54.6; H, 8.2; N, 37.1.

EXAMPLE VII 224 g. of 2,4-bis-(chloro)-6-propylmercapto-s-triazine was dissolved in 500 m1. of acetone and 98 g. of a-aminoisovaleronitrile added slowly while cooling to 10 to 15 C. A solution of 40 g. of NaOH in 100 ml. of H 0 was then added. The pH of the solution was between 7 and 8. Then 90 g. of a 50% ethylamine solution and 100 g. of a 40% NaOH in H O were added. The mixture was heated under a reflux condenser to 60 C. while stirring for 3 hours. The solvent was distilled off and the residue taken up in water. The thick crystal paste which formed was 7 further washed and dried to yield 282.5 g. of 2-(1-cyano- 1 methylpropyl)amino-4-ethylarnino-6-propylmercapt0- s-triazine, M.P. 71-72 C.

Analysis.C H N S, mol. wt. 294: Calculated (percent): C, 53.1; H, 7.5; N, 28.6; S, 10.9. Found (percent): C, 52.8; H, 7.2; N, 28.8; S, 10.6.

EXAMPLE VIII 12 g. of sodium cyanide and ml. of a 20% aqueous solution of trimethylamine were added, with stirring, to 50.9 g. of 2 (1 cyano-l-methylpropyl)amino-4-ethylamino-6-chloro-s-triazine in 300 ml. of tetrahydrofuran and the mixture heated between 50 C. for 3 hours. After evaporating the solution, Washing the residue with water, drying and crystallizing from a benzene-gasoline (1:1) mixture, there was obtained 24 g. of white crystalline 2 (1 cyano-l-methylpropyl)amino-4-ethylamino-6- cyano-s-triazine, M.P. 119-120" C.

PREFERRED EMBODIMENTS While the s-triazines of Formula I show some depressant effects in mammals, there are dilferences both quantitative and qualitative exhibited by individual members of the class. Especially preferred depressants because of their activity as analgesics, muscle relaxants, anticonvulsants, and/or tranquilizers are the s-triazines of Formula I wherein X is chloro, azido, cyano, OR or SR and more especially wherein R is alkyl of 1-4 carbon atoms, preferably methyl, ethyl, isopropyl or isobutyl; R is hydrogen or methyl; R is hydrogen; R is hydrogen,

8 methyl or ethyl; and X is chloro, azido, cyano, methoxy or methylthio.

Preferred s-triazines within this subclass are:

The following examples are presented to illustrate certain pharmacological responses induced by triazine compositions of the invention. These examples should in no way be regarded as limiting the scope of the invention.

The results of the various pharmacological responses tested are shown in Table I.

TABLE I Muscle relaxant Anticonvulsant response 8 tranquilization response Maximal Analgesic Pernicious electroshock response Muscle preening seizure Approximate lntrarelaxant antagonism antagonism Antistrychnine Approximate muscle peritoneal a rating based on based on response ratio analgesic relaxant analgesic at 100 ED ip. or ED i-p. or based on Test dose-Oral dose-Oral b rating at mg./kg. 32 mgJkg. 100 mgJkg. ED i.p. or compound mg./kg. rug/kg. mg./kg. i.p. i.p. i.p mg./kg. i.p

Analgesic response (a) The presence of an analgesic effect was identified as an absence of a struggling or phonating response to a manual pinch of the tail of treated mice. The laboratory white mice for each treatment were placed in individual compartments. The mice were orally intubated with the test compound at the dosage of 500 milligrams per kilogram, and 15 minutes, 1 hour, 2. hours, 4 hours and 24 hours after treatment a pinch of the tail was applied to each mouse. Any compound inducing an analgesic response in 50 percent of the mice at any of these test intervals was considered active in this test. Some of the compounds were tested at lower dosages.

While the exact safety factor has not been evaluated for all compounds of the invention, it has been found that the effective analgesic dose of the triazines of the invention is considerably lower than that toxic dose (LD Muscle relaxant response (b) As in (a) mice were orally intubated with the test compound and the muscle relaxant effects of the compounds were evaluated. The procedure for assessing skeletal muscle relaxant activity involves an evaluation of passivity, fiaccidity and pinnal reflex blockage. Passivity is defined as an absence of the struggle behavior of the animal when manipulated manually and may indicate skeletal muscle relaxation, central depression, tranquilization, paralysis, or anesthesia. Flaccidity is measured by the decreased tonus of skeletal musculature and may indicate myorelaxant activity, central depression, or paralysis. The pinnal reflex is tested by touching the inner aspects of the ear with a fine wire to elicit a characteristic ear twitch. An impairment of this reflex suggests an inhibition of polysynaptic reflexes.

Analgesic response-Intraperitoneal (c) The analgesic response was determined in laboratory white mice by injection of the triazines under test at an intraperitoneal dosage of 100 mg. per kg. The results were obtained by evaluation similar to that described for the Approximate-Analgesic DoseOral. The compounds were rated on a one plus to four plus scale. When 1-2 mice out of ten showed an analgesic response, a rating was assigned; ++i+ indicated that 3-6 out of ten mice responded; indicated that 7-9 out of ten responded; while a rating meant that all ten mice gave an analgesic response at the dosage tested.

Muscle re1axant-Tranquilization response (d) The muscle relaxant effects, as expressed by passivity, flaccidity and pinnal reflex blockage, were assessed in laboratory mice injected intraperitoneally with 100 mg./ kg. of the test compound as in (b). In addition the tranquilizing eflects of the compounds under test were evaluated by the pernicious preening test (Wilfon, J. G. et al., Fed. Proc. 18:20, 1960). The pernicious preening behavior was elicited by painting the rear of the mice with a pilocohesive dye. A violent unremitting tearing of the stiff, cohering strands of hair constitutes the pernicious preening behavior. Thirty minutes after injection, the pilocohesive dye was applied and the presence or absence of the compulsive behavior was noted for a 10 minute interval. The ratings for the muscle relaxant response are based upon the scale given in (c). Etfective antagonism of pernicious preening is shown with the same scale as in (c). That is, +==12 mice out of ten, ++=3-6 mice out of ten, +++=79 mice out of ten and ++++=10 mice out of ten responded. Some of these values for the individual triazines were determined at a dosage of 32 mg./ kg. while the others were determined on the basis of ED values, the dose at which 50 percent of the treated animals exhibit an effective response. These ED values were then translated into the 1+ to 4+ scale by the following criteria: ED values of 30100 mg./

Anticonvulsant response (e) The test procedures used were maximal electroshock and antistrychnine assay methods. The test compound was intraperitonally injected into laboratory mice and after 30 minutes the anticonvulsant activity was measured. The technique employed in the maximal electroshock method was essentially that of Swinyard, E. A., J. Amer. Pharm. Assoc. 38:201 (1949). The mice were subjected to an alternating current stimulus, about equal to three times the current necessary to produce maximal seizures, and prevention of the hindlimb tonic extensor phase was considered to be an effective anticonvulent action. In the antistrychnine assay, the mice were intraperitoneally injected with the test compound and then were challenged with a lethal intraperitoneal does of strychnine sulfate. Increase in survival time against the lethal action of strychnine of greater than three standard deviation of the control mean was considered an effective action. Anticonvulsant activity in these tests suggests skeletal muscle relaxation or eflicacy against epileptic seizures. Effective antagonism of maximal electroshock seizure and antistrychnine activity are given on the same 1+ to 4+ scale as in (c). Some of these values for the individual triazines in the maximal electroshock seizure test were determined at a dosage of mg./kg. while the others were determined on the basis of ED values, the dose at which 50 percent of the treated animals exhibited an effective response. These ED values were then translated into the 1+ to 4+ scale by the following criteria: ED values of 100-300 mg./kg.=+, 30-100 mg./kg.=++, 1030 mg./kg.=+++ and 10 mg./kg.=++++. The antistrychnine activities for the individual triazines were also determined in either of two ways. Some are based on the response ratio at *mg/kg. while the others on the ED values. The criteria for translating the ED values to the 1+ to 4+ scale is the same as for the maximal electroshock seizure test.

We claim as our invention:

1. A depressant veterinary and pharmaceutical composition comprising (a) compound of the formula wherein R is hydrogen or alkyl of 1-5 carbon atoms; R is hydrogen or alkyl of 1-3 carbon atoms; R is hydrogen, alkyl of 1-5 carbon atoms, alkoxy of 1-3 carbon atoms, methoxyalkyl of 2-5 carbon atoms or w-alkenyl of 3-5 carbon atoms; R is hydrogen or alkyl of l-3 carbon atoms; and X is -CCl Cl, NHR N S-R -CN or --OR and R R and R are alkyl of 1-3 carbon atoms and (b) a physiologically acceptable carrier, the percent by weight of (a) in the total formulation being from from about one to about 95. 2. The veterinary and pharmaceutical composition of claim 1 wherein X is chloro, azido, cyano, -OR or -SR 3. The veterinary and pharmaceutical composition of claim 2 wherein R is alkyl of 1-4 carbon atoms, R is hydrogen or methyl, R is hydrogen, R is hydrogen, methyl or ethyl and X is chloro, azido, cyano, methoxy or methylthio.

4. The veterinary and pharmaceutical composition of claim 3 wherein R is isobutyl, R and R are methyl, and. X is chloro.

5. The veterinary and pharmaceutical composition of claim 3 wherein R is isopropyl, R and R are methyl and X is azido.

6. The veterinary and pharmaceutical composition of claim 3 wherein R and R are methyl, R is ethyl and X is cyano.

7. The veterinary and pharmaceutical composition of claim 3 wherein R is methyl, R is hydrogen, R is ethyl and X is methoxy.

8. The veterinary and pharmaceutical composition of claim 3wherein R is isopropyl, R and R are methyl and X is methylthio.

9. A method of inducing a depressant repsonse in mammals comprising administering to said mammal in need thereof an effective dosage of a compound of the formula NRzRa wherein 10. The method of claim 9 wherein said compound is administered orally to said mammal.

11. The method of claim 9 wherein said compound is administered parenterally to said mammal.

12. The method of claim 9 wherein X is chloro, azido, cyano, OR or SR 13. The method of claim 12 wherein R is alkyl of 14 carbon atoms, R is hydrogen or methyl, R is hydrogen, R is hydrogen, methyl or ethyl and X is chloro, azido, cyano, methoxy or methylthio.

14. The method of claim 13 wherein R is isobutyl, R and R are methyl, and X is chloro.

15. The method of claim 13 wherein R is isopropyl, R and R are methyl and X is azido.

16. The method of claim 13 wherein R and R are methyl, R is ethyl and X is cyano.

17. The method of claim 13 wherein R is methyl, R is hydrogen, R is ethyl and X is methoxy.

18. The method of claim 13 wherein R is isopropyl, R and R are methyl and X is methylthio.

References Cited UNITED STATES PATENTS 2,867,621 1/1959 Grundmann 260249.5

2,909,420 10/1959 Gysin et a1. 260249.5

3,086,855 4/1963 Knusli et al 260249.9

FOREIGN PATENTS 1,329,306 4/-963 France 260249.5

ALBERT T. MEYERS, Primary Examiner DAREN M. STEPHENS, Assistant Examiner 

